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Yuka Kobayashi, Tomoko Orita, Chiemi Yamashiro, Syohei Uchi, Makoto Hatano, Masaaki Kobayashi, Kazuhiro Tokuda, Ryoji Yanai, Atsunobu Takeda, Tatsuro Ishibashi, Koh-hei Sonoda, Kazuhiro Kimura; Inhibitional effect of TGF-β2-induced EMT in RPE cells by an RAR-γ agonist. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4003.
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The fibrotic reaction mediated by retinal pigment epithelial (RPE) cells contributes to the loss of vision associated with age-related macular degeneration (AMD). We examined the role of retinoic acid receptor-γ (RAR-γ) in the epithelial-mesenchymal transition (EMT) and other processes of fibrosis in mouse retinal pigment epithelium (RPE) cells and subretinal fibrosis mouse model.
Primary mouse RPE cells cultured in a type I collagen gel were incubated with or without transforming growth factor-β2 (TGF-β2) and the RAR-γ agonist R667. Collagen gel contraction was determined by measurement of gel diameter. Expression of α–smooth muscle actin (α-SMA), mitogen-activated protein kinases, Smad2, matrix metalloproteinases (MMPs) was examined by immunoblot analysis. Fibronectin and interleukin-6 (IL-6) secretion was measured with immunoassays. Immunohistofluorescence analysis with antibodies to glial fibrillary acidic protein and type I collagen was performed with subretinal fibrosis mouse model in vivo.
The RAR-γ agonist R667 inhibited TGF-β2-induced collagen gel contraction mediated by the RPE cells in a concentration- and time-dependent manner. Expression of the mesenchymal markers α-SMA and fibronectin, the release of IL-6, and mitogen-activated protein kinases, and Smad2, induced by TGF-β2 were inhibited by R667. TGF-β2–induced release of MMP-2, MMP-3, MMP-8, and MMP-9 from RPE cells was also suppressed by the RAR-γ agonist. Immunohistofluorescence analysis with antibodies to glial fibrillary acidic protein and type I collagen showed that R667 inhibited the development of subretinal fibrosis in a mouse model in vivo.
Our observations suggest that RAR-γ signaling may play a key role in the pathogenesis of subretinal fibrosis associated with AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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